Local anesthetic base and solution and their manufacture



Patented Dec. 13, 1938 UNITED STATES PATENT OFFICE LOCAL AN'ESTHE'IICBASE AND SOLUTION AND THEIR MANUFACTURE No Drawing. Application October5, 1935,

Serial No. 43,713

12 Claims.

This invention relates to local anesthetic bases and solutions and theirmanufacture.

Procaine is the accepted local anesthetic for hypodermic injection. Itis usually employed as the hydrochloride salt which is soluble in water;If injected alone in small doses hypodermically, the anesthetic iscarried away by the arteries and capillaries and oxidized by the bodywithin'15 minutes. Under such circumstances anesthesia, although itoccurs, is neither profound nor prolonged enough for surgical purposes.

caine alone under the above circumstances, profuse bleeding occurs.

To prevent this epinephrin or a similar vasoconstrictor is combined instandard practice With procaine hydrochloride in water solution. Itsaction is to contract the capillaries and arterioles and thus tolocalize the local anesthetic at the point of its introduction by thehypodermic needle and at the same time to minimize bleeding.

The usual dose for a single hypodermic injection is about 2 cc. of a 2%solution of procaine hydrochloride which, therefore, contains about 0.04gr. of the anesthetic. With this is ordinarily employed approximately.002.005% of epinephrin. These concentrations will give suflicientanesthesia for the usual operation. If the percent of epinephrin isreduced below .002% the solution becomes substantially ineifective as ananesthetic. It is important for anesthetic purposes to employ as smallquantities of materials producing anesthesia and -vaso-constriction aspossible to produce the desired effects, in order p to minimize theafter effects of the ingredients injected, all of which must be consumedin some way by the body.

Procaine is valueless as a surface anesthetic such as required in eyeoperations requiring a. 10% solution as compared with the usual 2%solution for hypodermic use. I i The principal object of the presentinvention accordingly is to produce a series of local anesthetic basesand solutions having relatively Furthermore there is no control ofhemorrhage and if surgery is attempted using proother object is toprovide simple methods for manufacturing these substances.

The invention comprises the novel products as Well as the novelprocesses and steps of processes according to which such products aremanufactured, the specific embodiments of which are describedhereinafter by way of example and in accordance with which I now preferto practice the invention.

I have found in accordance with my invention that the mono alkyl aminoethyl para amino benzoates, having the formula NH2C6H4COOC2H4NH alkyl,are superior in their action to the standard anesthetics. I have foundthat these substances having this formula when used hypodermically insingle doses may be employed with a vaso-constrictor in smaller amountswith respect to both the anesthetic and the vaso-constrictor, than inthe standard solutions of procaine hydrochloride now on the market, toproduce the same or greater anesthetic effects. I have found that I mayadd less epinephrin than can be employed with procaine to these newsolutions to produce the same or greater anesthetic efiect' thanproduced by the ordinary combinations of procaine hydrochloride andepinephrin. In addition I have indications that in some instances theepinephrin or other vaso-constrictor may be entirely omitted.

In accordance with my invention I have found that the mono alkyl aminoethyl para amino benzoates can be prepared by combining a mono .alkylamino ethanol with para nitro benzoyl chloride to form a mono alkylamino ethyl para nitro benzoate, which is then reduced by hydrogen orother reducing agent to form a mono alkyl amino ethyl para aminobenzoate. In order to carry out this process it is necessary accordinglyto secure the intermediate ethanols. I accordingly will describe themethods employed for producing these ethanol intermediates as follows:

1. The production of normal mono propyl amino ethanol oily layerextracted with ether, which caused. a;

complete separation from any unreacted ethanolamine, which is insolublein ether. The ethereal layer was dried over sodium hydroxide anddistilled. The normal mono propyl amino ethanol distilled without anyforerunnings at a tempera-, ture of 181 C. There was no high boilingresidue and the yield was 39 grams, or 67% of theory.

-. 2. The preparation of normal mono butyl amino ethanol The preparationof this substance follows the same procedure as given for normal propylamino ethanol with the exception of the quantityof materials used andthe use of the normal butyl amine as the starting material. The normalmono butyl amino ethanol distllls without any forerunning at atemperature of 198 C. and there is no high boiling residue and the yieldis 65% of theory.

3. The preparation of mono isobutyl amino e ethanol 'The preparation ofthis substance follows the same procedure as given, for normal propylamino ethanol with the exception of the quantity of materials used andthe use of the isobutyl amine as the starting material. The normal monoisobutyl amino ethanol distills without any forerumiing at a temperatureof 186 C. and there is no high boiling residue and the yield is 60% oftheory.

4. The preparation of mono normal amyl amino ethanol 149 grams of normalmono butyl aniline to which is added directly 40 grams (or .95 mol) ofethylene oxide. The flask was immediately stoppered and well shaken. Itwas then allowed to stand at room temperature for about three weeks.

At. the end 01 this time the contents f the flask were transferred to a.distilling flas and distilled. The yield of butyl hydroxy ethyl anilinewas quantitative. There was no low boiling fraction. The yield was 155grams or 96% of theory. Boiling point 300 at 760 millimeters. To grams(1 mol) of butyl hydroxy ethyl aniline thus prepared was added 19 gramsof hydrochloric acid (2 mols) and the mixture cooled to 5 C. Whileagitated 1 mol of sodium nitrite was added slowly until the test withstarch iodide paper indicated a slight excess of nitrous oxide. Thenitrosated material was then dropped slowly on a boiling solution of 50%sodium hydroxide and steam-distilled. The steam distillation wascontinued until the distillate was no longer cloudy. The distillate wasthen extracted with ether, the ether dried and distilled. The yield was10 grams of the normal mono butyl amino ethanol boiling at propyl-, themono-isopropyland the mono-ethyl amino ethanol.

The condensation of the secondary amino alcohols just mentioned proceedssmoothly when reacted under proper conditions. Reaction is as follows:

COCH-OHCHgCHgNHR oooomcrnNnn N0, No,

It is important that the co ditions be such that the hydrogen of thehydroxyl group of the secondary amino alcohols shall be replaced.Otherwise the hydrogen may be eliminated from the amine group leavingthe hydroxyl group unaffected, or a second molecule of para nitrobenzoyl chloride may take partin the reaction, these side reactionsproducing difierent products from those'represented in the aboveequation. If the temperature is raised too high, the above reactionfails and para nitro benzoyl chloride is sapo-m'fied into para nitrobenzoic'acid. Since the condensation with the nitrogen group yields asubstituted amide, \upon raising the temperature the amide is alsosaponified to the para nitro benzoic acid and the secondary aminoalcohol is regained. This saponification occurs through the presence ofsodium hydroxide. In addition. the quantity of sodium hydroxide isessentially the same for all oi the reactions involving the alkyl aminoethanols used. If the temperature is kept too low, the reactionindicated by the equation above may take place partially but in additionthere will be a reaction with two molecules of the para nitrobenzoylchloride.

When alkyl amino alcohols below butyl amino ethanol are used, the paranitro benzoyl chloride should be added in small quantities to theaqueous solution to avoid sapom'flcation of the para nitro benzoylchloride. The reaction materials are preferably used in molecularequivalents since an excess of para nitro benzoyl chloride isdetrimental to the reaction.

The following is the preferred procedure which is used in effectingcondensations producing local anesthetic bases in accordance with myinvention: The preparation of the mono normal butyl amino ethyl paraamino benzoate,

NH, 10 grams of mono normal butyl amino ethanol,

"16 grams of para nitro benzoyl chloride and 5 grams of sodium hydroxidein 175 cc. of water were allowed to react. The temperature wasmaintained between 30 to 40 C. during reaction.

sponded positively when tested for the presencev of the amineconfiguration and also the nitro group. The yellow viscous oil which wasformed was mono-butyl amino ethyl para nitro benzoate.

20 grams of this latter material was directly reduced with 15 grams oftin and 50 cc. of concentrated hydrochloric acid. The temperatureof thereduction was controlled by addition from time to time of smallquantities of cold water to maintain the temperature at or near 70 C.When the reaction was completed 150 cc. of sodium hydroxide was addedand the solution then cooled to 15 C. The oil which gradually formedcombined with undissolved tin to form a pasty mass which soon settled.The supernatant liquid was decanted and the residue washed two or threetimes with water to remove all traces of alkali. The oily mass,freed.from most of its water, was then extracted with ether andfiltered. The filtrate was evaporated to dryness and the yield of thebase obtained was 13 grams or 73.5% of theory. In order to get themelting point of the base, the mono-hydrochloride was first formed andpurified, then the hydrochloride was dissolved in water and justneutralized with ammonia water. The colorless oil formed sooncrystallized into a white solid, which after filtration and air drying,had a melting point of 74 to 74.5" C. The hydrochloride was made whenthe oily base was dissolved in. propyl alcohol and the calculatedquantity of aqueous hydrochloric acid added to form themono-hydrochloride of this compound. After repeated recrystallizations,a white needle crystal was formed which had a melting point at 146 C.

The mono isobutyl amino ethyl para' amino benzoate, the n-mono amylamino ethyl para amino benzoate and the mono isoamyl amino ethyl paraamino benzoate are prepared in a similar manner to that just described,withv suitable well-known variation in the quantity of the reactingmaterials according to 'their'molecular weights. The following are theproperties of the compounds just mentioned as determined by In additionto the amyl and butyl derivatives mentioned above, my work indicatesthat the corresponding propyl derivatives, for example mono propyl aminoethyl para amino benzoate also has similar properties to these materialsdescribed above and apparently it has a high anesthetic efliciency.

The group of hydrochloride salts of mono alkyl amino ethyl p-aminobenzoates just described form definite crystals with sharp meltingpoints. They are all soluble in water and ethyl alcohol and sparinglysoluble in propyl alcohol. bases, on reprecipitation, formed whitepowdery flakes, insoluble in water, but readily soluble in acetone,ethyl alcohol and benzene, and soluble in an excess of ether.

All the bases, before being converted to the hydrochloride, werestrongly anesthetic to the tongue. chloride, it. was foundthat all thesecompounds seemed to retain their anesthetic properties when tested bythe tongue. They difler in this respect from procaine hydrochloride,since that salt has no anesthetic efiect whatsoever when placed upon-The After their conversion to the hydro-- noted below this was found tobe the case. In

testing for these properties the procedure of Sollmann (Journal ofPharmacology and Experimental Therapeutics, 1918, and his handbook) wasfollowed. These tests were the following:

Since their behavior under test conditions is well established, cocaine,butyn, procaine and epinephrin were the criteria used to prove theaccuracy of the technique and to ail'ord a baseline against which thenew compounds were standardized.

Results of Test No. 1 for the conduction anesthesia on the sciatic nerveof a frog shows as follows: In accordance with this test the mono amyl'amino ethyl para aminobenzoate and the mono iso-amyl amino ethyl paraamino benzoate were about four times as strong as procaine. The monoisobutyl amino ethyl para amino benzoate as an anesthetic was aboutthree times as strong as procaine and mono butyl ethyl amino .para

. amino benzoate was equivalent to procaine in strength.

Test No. 2.Surface anesthesia on the surface of a frogs leg showed thatmono amyl amino ethyl para amino benzoate and mono iso-amyl amino ethylpara amino benzoate were practically four times as strong as cocaine;mono butyl ethyl amino para amino benzoate and mono isobutyl amino ethylpara amino benzoate about one-half as strong-as cocaine as asurfaceanesthetic. (b) Surface anesthesia of the same relative strengthas obtained on the frog's leg was also obtained on the cornea of therabbit's eye. 7

Test No. 3.The intracutaneous or wheal method showed that mono isobutylamino ethyl para amino benzoate, mono amyl amino ethyl para aminobenzoate and mono iso-amyl amino ethyl para amino benzoate were fourtimes as strong as procaine and mono butyl amino ethyl para aminobenzoate twice as strong as procaine.

Test No. 5.Vaso-constriction by means of the arterial spirals indicatethat at certain concen- 'trations mono amyl amino ethyl para aminobenzoate and mono iso-amyl amino ethyl para amino benzoate exhibitthisproperty.

From the above it will be noted that the mono 'allryl amino ethyl paraamino benzoates possess excellent anesthetic properties, some 01' themembers of the series also exhibiting vase-constrictor action. Thetoxicity of these compounds is relatively low especially inconsideration of their high anesthetic potency.

The local anesthetics herein described are compatible with epinephrinand may be employed therewith in water solution. Those anesthetics whichhave a vase-constrictor action as herein described may be employedwithout epinephrin' where anesthetic concentration in the-dose given isa suflicient concentration to produce'the desired constriction ofthe-arterioles, or capillary walls. If the anesthetic concentration isinsuflicient for this purpose, I prefer to add epinephrin or othercompatible vase-constrictor to produce a proper constrictive effect forlocal" anesthesia.

The following are specific examples of the use of anesthetic solutionsaccording to my invention: 5 grams of mono amyl ethyl amino ethyl paraamino benzoate hydrochloride with 6 grams of sodium chloride aredissolved in sumcient water to make one liter. Epinephrin is added tothe extent of one part per 100,000. 1 gram of sodium bisulfite is addedper liter. The solution as prepared above is suitable forsubcutaneousinjection.

Instead of mono amyl ethyl amino ethy D a amino benzoate hydrochlorideused in the above example, I may substitute any one of the otheranesthetics mentioned-mono isobutyl amino ethyl para amino benzoate,mono butyl amino ethyl para amino benzoate, mono iso-amyl amino ethylpara amino benzoate, using the same proportion namely 5 grams per literas mentioned in the above example.

' For surface'anesthesia I prefer to use the following formula: lo'gramsof mono normal amyl amino ethyl para amino benzoate hydrochloride, 6grams of sodium'chloride .dissolved in sufllcient water to make oneliter of solution. In place of the mono normal amyl I have also employedthe mono iso-amyl amino ethyl para amino benzoate in the same proportionas employed in the above example for surface anesthesia.

The solutions described have been employed by me to give successfullocal anesthesia.

The expression mono butyl amino as employed in the claims is intended tocover both mono normal butyl amino compounds as well as compoundscontaining the isomers of the mono butyl group. Similarly theexpressions monoamyl amino and mono propyl amino" are intended to coverboth the normal compounds and the isomers thereof. The expression monolower alkyl amino ethyl amino benzoate is used-to cover not only thecompounds herein specifically given as the preferred form of myinvention, but as well compounds having the same general properties asmy preferred compounds for the purpose stated.

, In the claims where the compound a mono alkyl amino ethyl para aminobenzoate or similar compound is claimed, it is intended'not only 'tocover this compound, which is not easily soludetails and formssince manychanges and modifications may be made and the invention embodied inwidely different forms without departing from the spirit and scopethereof in its broader aspects. Hence I desire to cover allmodifications, forms and embodiments comingethyl para amino benzoatehaving the formula.

NH2CeH4COOC2H4NH alkyl, in which the alkyl group contains not more thanfive carbon atoms in the chain.

5. An anesthetic solution containing a salt of a mono alkyl amino ethylpara amino benzoate in which the alkyl radical is a derivative of alower aliphatic hydrocarbon dissolved in water.

6. An anesthetic solution containing a salt of a mono alkyl amino ethylpara amino benzoate, in which the alkyl group contains not more thanfive carbon atoms in the chain dissolved in water. a 7. An anestheticsolution containing a salt of a mono amyl amino ethyl para aminobenzoate, dissolved in water.

8. An anesthetic solutioncontaining a salt of a mono butyl amino ethylpara amino benzoate, dissolved in water. 7

9. A process for the preparation of a local anesthetic which comprisescombining a mono alkyl amino ethanol in which the alkyl radical is aderivative of a lower aliphatic hydrocarbon with para nitro behzoylchloride to form the mono alkyl amino ethyl para nitro benzoate andreducing the nitro compound to form the mono alkyl amino ethyl paraamino benzoate.

10. An anesthetic solution containing a-salt of a monoalkyl amino ethylpara amino benzoate, in which the alkyl group contains not more thanfive carbon atoms in the chain, and vasoconstrictive material.

11. An anesthetic solution containing a salt of a mono alkyl aminoetliyl para amino benzoate, in which the alkyl group contains not morethan flve carbon atoms in the chain, and less than 0.002% of epinephrin.

12. As a new compound a mono propyl amino ethyl amino benzoate havingthe formula NH2CeH4COOC2H4NHCaH'z.

SAMUEL D. GOLDBERG.

. CERTIFICATE OF CORRECTION. Patent No. 2,1 9,818. December 1 19 8.

V SAMUEL D. GOLDBERG. It is hereby certified that error appears in theprinted specification of the above numberedpatent requiring correctionas follows: Page h, second column, line 16, claim '5, for "par amino"read para amino; lines H2 and 1 ,3, c1ain 1'9, before "mono" insertcorresponding; and that the said Letters Patent should be read with thiscorrection therein that the-same may conform to the recordof the case inthe Patent Office.

Signed and sealed this 51st day of January, A. D. 1959.

Henry Van Arsdale I 7 Acting Commissioner of Patents.

